HIV prevalence in sub-Saharan Africa is highest of any global region and many infections occur among youth ages 15-24 years. Comprehensive HIV prevention in high-burden sub-Saharan African settings must address both HIV and pregnancy among young females, and HIV prevention strategies among males, using evidence-based approaches in combination. Settings such as Nyanza Province, western Kenya where there is high HIV prevalence, high fertility rates, early onset of sex, frequent intergenerational sex and low circumcision prevalence are a high priority for developing and evaluating multi-component HIV prevention with a focus on young men and women in order to have a large population impact. Our team of biobehavioral and clinical scientists, mathematical modelers, and trial design specialists will: Identify gender (sex)-specific drivers of HIV acquisition risk, including pregnancy among females, for youth in sub-Saharan Africa, and interventions to best address those risks (Aim 1). Conduct mathematical modeling to select optimal combination intervention package components and to assess potential population-level impact (Aim 2). In partnership with a highly-productive nongovernmental organization (NGO) that is delivering PEPFAR-funded HIV prevention services, develop and pilot a combination HIV prevention package specific for female and for male youth - 'MP3-Youth' - in Migori district, Nyanza Province (Aim 3). We will deliver the MP3-Youth package using community-based mobile health teams with the NGO. All youth attending the mobile health events will complete an audio computer-assisted self-interview survey. A randomly-selected subset of n=200 youth will be followed longitudinally at 6- and 12- months using cell phone text message surveys to prospectively assess prevention method uptake, adherence, and risk compensation behaviors. Design a phase IV study protocol for testing the effectiveness of a gender-specific youth HIV prevention package in sub-Saharan Africa (Aim 4). We will disseminate these research protocol recommendations, and study instruments including the mathematical modeling tool, as a combination prevention intervention research toolkit. The MP3-Youth study will provide critical information for design and evaluation of combination HIV prevention intervention packages that are sensitive to gender-specific risks among this most-at-risk population in high-HIV burden African settings. PUBLIC HEALTH RELEVANCE: The study addresses a most-at-risk population (youth in sub-Saharan Africa) and the need for gender-specificity in combination HIV prevention intervention selection, transmission impact modeling, and phase IV effectiveness study designs. This study will leverage a PEPFAR-funded HIV prevention program delivery infrastructure in western Kenya to pilot a combination HIV prevention package for youth leading to an optimal population-impact study protocol. A translational science package will be created and disseminated that others can use to conduct epidemiologic reviews, mathematical modeling, and study design for combination HIV prevention research in their settings.